Suppressed tumorigenicity of human endometrial cancer cells by the restored expression of the DCC gene

To obtain functional evidence for DCC as a tumour suppressor associated with endometrial cancer, the human DCC cDNA encoding a complete open reading frame (ORF) was transfected into highly tumorigenic human endometrial carcinoma cells, HHUA and Ishikawa in which DCC expression was completely deleted. Reconstituted expression of DCC in HHUA had little effect on in vitro growth, but suppressed tumour formation in mice completely. The clones from Ishikawa had abundant DCC expression similar to that in normal endometrium. Their growth in vitro was suppressed and showed apoptotic phenotype. Lower levels of DCC expression in the prolonged passaged clones did not induce apoptosis, but still had the potential to suppress tumorigenicity. These observations imply a role of DCC in regulation of normal endometrial cell growth, and categorize DCC as the tumour suppressor gene for endometrial cancer. © 2000 Cancer Research Campaign

[1]  Y. Takagi,et al.  Somatic alterations of the DPC4 gene in human colorectal cancers in vivo. , 1996, Gastroenterology.

[2]  P. Chomczyński,et al.  Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. , 1987, Analytical biochemistry.

[3]  N. Wake,et al.  DCC gene alteration in human endometrial carcinomas , 1994, International journal of cancer.

[4]  S. Brewster,et al.  Loss of heterozygosity on chromosome 18q is associated with muscle-invasive transitional cell carcinoma of the bladder. , 1994, British Journal of Cancer.

[5]  R. Weinberg,et al.  Phenotype of mice lacking functional Deleted in colorectal cancer (Dec) gene , 1997, Nature.

[6]  Scott E. Kern,et al.  Evaluation of candidate tumour suppressor genes on chromosome 18 in colorectal cancers , 1996, Nature Genetics.

[7]  L. Hedrick,et al.  DCC genetic alterations and expression in endometrial carcinoma. , 1997, Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc.

[8]  M. Masu,et al.  Deleted in Colorectal Cancer (DCC) Encodes a Netrin Receptor , 1996, Cell.

[9]  R. Weinel,et al.  Frequent loss of expression of the potential tumor suppressor gene DCC in ductal pancreatic adenocarcinoma. , 1992, Cancer research.

[10]  Kathleen R. Cho,et al.  The DCC gene product in cellular differentiation and colorectal tumorigenesis. , 1994, Genes & development.

[11]  M. Saegusa,et al.  Loss of expression of the gene deleted in colon carcinoma (DCC) is closely related to histologic differentiation and lymph node metastasis in endometrial carcinoma , 1999, Cancer.

[12]  Suna Wang,et al.  Infrequent DPC4 gene mutation in esophageal cancer, gastric cancer and ulcerative colitis-associated neoplasms. , 1996, Oncogene.

[13]  A. Montag,et al.  Evidence for a Common Molecular Pathogenesis in Colorectal, Gastric, and Pancreatic Cancer , 1991, Genes, chromosomes & cancer.

[14]  D. Grignon,et al.  Frequent loss of expression and loss of heterozygosity of the putative tumor suppressor gene DCC in prostatic carcinomas. , 1993, Cancer research.

[15]  G. Nicolson,et al.  Involvement of Integrin αvβ3 in Cell Adhesion, Motility, and Liver Metastasis of Murine RAW117 Large Cell Lymphoma , 1996 .

[16]  V. Marder,et al.  NF-kappa B-dependent inhibition of apoptosis is essential for host cellsurvival during Rickettsia rickettsii infection. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[17]  M. Inoue,et al.  Loss of expression and loss of heterozygosity in the DCC gene in neoplasms of the human female reproductive tract. , 1995, British Journal of Cancer.

[18]  M. Oshimura,et al.  Suppression of endometrial carcinoma cell tumorigenicity by human chromosome 18 , 1995, Genes, chromosomes & cancer.

[19]  K. Miyake,et al.  Alterations in the deleted in colorectal carcinoma gene in human primary leukemia. , 1993, Blood.

[20]  E. White,et al.  Life, death, and the pursuit of apoptosis. , 1996, Genes & development.

[21]  Kathleen R. Cho,et al.  The DCC gene: structural analysis and mutations in colorectal carcinomas. , 1994, Genomics.

[22]  S. Miyamoto,et al.  Chromosomal deletions and K‐ras gene mutations in human endometrial carcinomas , 1992, International journal of cancer.

[23]  B. Mossman,et al.  Transcriptional activation of the proto-oncogene c-jun by asbestos and H2O2 is directly related to increased proliferation and transformation of tracheal epithelial cells. , 1995, Cancer research.

[24]  M. Loda,et al.  The DCC protein and prognosis in colorectal cancer. , 1996, The New England journal of medicine.

[25]  Kathleen R. Cho,et al.  Identification of a chromosome 18q gene that is altered in colorectal cancers. , 1990, Science.

[26]  Shahrooz Rabizadeh,et al.  The DCC gene product induces apoptosis by a mechanism requiring receptor proteolysis , 1998, Nature.

[27]  M. Takeichi,et al.  The cadherins: cell-cell adhesion molecules controlling animal morphogenesis. , 1988, Development.

[28]  E. Fearon,et al.  Expression and alternative splicing of the deleted in colorectal cancer (DCC) gene in normal and malignant tissues. , 1994, Cancer research.

[29]  Timothy E. Kennedy,et al.  Netrins are diffusible chemotropic factors for commissural axons in the embryonic spinal cord , 1994, Cell.

[30]  M. Oshimura,et al.  Transfer of a normal human chromosome 11 suppresses tumorigenicity of some but not all tumor cell lines , 1990, Journal of cellular biochemistry.

[31]  L. Hedrick,et al.  The DCC gene suppresses the malignant phenotype of transformed human epithelial cells. , 1995, Oncogene.

[32]  Hao Wang,et al.  Netrin-1 Is Required for Commissural Axon Guidance in the Developing Vertebrate Nervous System , 1996, Cell.

[33]  P. Devilee,et al.  Somatic genetic changes on chromosome 18 in breast carcinomas: is the DCC gene involved? , 1991, Oncogene.

[34]  S. Coons,et al.  Expression of the tumor suppressor gene DCC in human gliomas. , 1993, Cancer research.